Effect of aging on the human myometrium at single-cell resolution.
Journal
Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555
Informations de publication
Date de publication:
31 Jan 2024
31 Jan 2024
Historique:
received:
17
07
2023
accepted:
17
01
2024
medline:
1
2
2024
pubmed:
1
2
2024
entrez:
31
1
2024
Statut:
epublish
Résumé
Age-associated myometrial dysfunction can prompt complications during pregnancy and labor, which is one of the factors contributing to the 7.8-fold increase in maternal mortality in women over 40. Using single-cell/single-nucleus RNA sequencing and spatial transcriptomics, we have constructed a cellular atlas of the aging myometrium from 186,120 cells across twenty perimenopausal and postmenopausal women. We identify 23 myometrial cell subpopulations, including contractile and venous capillary cells as well as immune-modulated fibroblasts. Myometrial aging leads to fewer contractile capillary cells, a reduced level of ion channel expression in smooth muscle cells, and impaired gene expression in endothelial, smooth muscle, fibroblast, perivascular, and immune cells. We observe altered myometrial cell-to-cell communication as an aging hallmark, which associated with the loss of 25 signaling pathways, including those related to angiogenesis, tissue repair, contractility, immunity, and nervous system regulation. These insights may contribute to a better understanding of the complications faced by older individuals during pregnancy and labor.
Identifiants
pubmed: 38296945
doi: 10.1038/s41467-024-45143-z
pii: 10.1038/s41467-024-45143-z
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
945Subventions
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : CP19/00162
Organisme : Ministry of Economy and Competitiveness | Instituto de Salud Carlos III (Institute of Health Carlos III)
ID : PI20/00942
Organisme : Regional Government of Valencia | Conselleria d'Educació, Investigació, Cultura i Esport (Conselleria d'Educació, Investigació, Cultura i Esport de la Generalitat Valenciana)
ID : FDEGENT/2019/010
Organisme : EC | EU Framework Programme for Research and Innovation H2020 | H2020 European Institute of Innovation and Technology (H2020 The European Institute of Innovation and Technology)
ID : 874867
Informations de copyright
© 2024. The Author(s).
Références
Beard, J. R. et al. The World report on ageing and health: A policy framework for healthy ageing. Lancet 387, 2145–2154 (2016).
pubmed: 26520231
doi: 10.1016/S0140-6736(15)00516-4
Kontis, V. et al. Future life expectancy in 35 industrialised countries: projections with a Bayesian model ensemble. Lancet 389, 1323–1335 (2017).
pubmed: 28236464
pmcid: 5387671
doi: 10.1016/S0140-6736(16)32381-9
Wu, Y., Li, M., Zhang, J. & Wang, S. Unveiling uterine aging: Much more to learn. Ageing Res Rev. 86, 101879 (2023).
pubmed: 36764360
doi: 10.1016/j.arr.2023.101879
Ledford, H. How the run-up to menopause changes the brain. Nature 617, 25–27 (2023).
pubmed: 37138117
doi: 10.1038/d41586-023-01474-3
Say, L. et al. Global causes of maternal death: A WHO systematic analysis. Lancet Glob. Health 2, e323–e333 (2014).
pubmed: 25103301
doi: 10.1016/S2214-109X(14)70227-X
Hoyert L. D. Maternal Mortality Rates in the United States, 2019. https://stacks.cdc.gov/view/cdc/103855 https://doi.org/10.15620/cdc:103855 (2021).
Bornstein, E., Eliner, Y., Chervenak, F. A. & Grünebaum, A. Concerning trends in maternal risk factors in the United States: 1989–2018. EClinicalMedicine 29–30, 100657 (2020).
pubmed: 34095788
pmcid: 8164172
doi: 10.1016/j.eclinm.2020.100657
Main, D. M., Main, E. K. & Moore, D. H. The relationship between maternal age and uterine dysfunction: A continuous effect throughout reproductive life. Am. J. Obstet. Gynecol. 182, 1312–1320 (2000).
pubmed: 10871444
doi: 10.1067/mob.2000.106249
Romero, R., Dey, S. K. & Fisher, S. J. Preterm labor: One syndrome, many causes. Science (1979) 345, 760–765 (2014).
Moreno, I. et al. The human periconceptional maternal-embryonic space in health and disease. Physiol. Rev. 103, 1965–2038 (2023).
pubmed: 36796099
doi: 10.1152/physrev.00050.2021
Rosenthal, A. N. & Peterson-Brown, S. Is there an incremental rise in the risk of obstetric intervention with increasing maternal age? Br. J. Obstet. Gynaecol. 105, 1064–1609 (1998).
pubmed: 9800928
doi: 10.1111/j.1471-0528.1998.tb09937.x
Jones, R. C. et al. The Tabula Sapiens: A multiple-organ, single-cell transcriptomic atlas of humans. Science (1979) 376, eabl4896 (2022).
Pique-Regi, R. et al. A single-cell atlas of the myometrium in human parturition. JCI Insight 7, e153921 (2022).
pubmed: 35260533
pmcid: 8983148
doi: 10.1172/jci.insight.153921
Goad, J. et al. Single-cell sequencing reveals novel cellular heterogeneity in uterine leiomyomas. Hum. Reprod. 37, 2334–2349 (2022).
pubmed: 36001050
pmcid: 9802286
doi: 10.1093/humrep/deac183
Karlsson, M. et al. A single-cell type transcriptomics map of human tissues. Sci. Adv. 7, eabh2169 (2021).
pubmed: 34321199
pmcid: 8318366
doi: 10.1126/sciadv.abh2169
Jin, S. et al. Inference and analysis of cell-cell communication using CellChat. Nat. Commun. 12, 1088 (2021).
pubmed: 33597522
pmcid: 7889871
doi: 10.1038/s41467-021-21246-9
Buechler, M. B. et al. Cross-tissue organization of the fibroblast lineage. Nature 593, 575–579 (2021).
pubmed: 33981032
doi: 10.1038/s41586-021-03549-5
Mitchell, T. S., Bradley, J., Robinson, G. S., Shima, D. T. & Ng, Y. S. RGS5 expression is a quantitative measure of pericyte coverage of blood vessels. Angiogenesis 11, 141–151 (2008).
pubmed: 18038251
doi: 10.1007/s10456-007-9085-x
Witze, E. S. et al. Wnt5a directs polarized calcium gradients by recruiting cortical endoplasmic reticulum to the cell trailing edge. Dev. Cell 26, 645–657 (2013).
pubmed: 24091015
doi: 10.1016/j.devcel.2013.08.019
Calcinotto, A. et al. Cellular Senescence: Aging, Cancer, and Injury. Physiol. Rev. 99, 1047–1078 (2019).
pubmed: 30648461
doi: 10.1152/physrev.00020.2018
Davidson, S. et al. Fibroblasts as immune regulators in infection, inflammation and cancer. Nat. Rev. Immunol. 21, 704–717 (2021).
pubmed: 33911232
doi: 10.1038/s41577-021-00540-z
Dorrier, C. E., Jones, H. E., Pintarić, L., Siegenthaler, J. A. & Daneman, R. Emerging roles for CNS fibroblasts in health, injury and disease. Nat. Rev. Neurosci. 23, 23–34 (2022).
pubmed: 34671105
doi: 10.1038/s41583-021-00525-w
Seals, D. R., Jablonski, K. L. & Donato, A. J. Aging and vascular endothelial function in humans. Clin. Sci. 120, 357–375 (2011).
doi: 10.1042/CS20100476
Arrowsmith, S., Robinson, H., Noble, K. & Wray, S. What do we know about what happens to myometrial function as women age? J. Muscle Res Cell Motil. 33, 209–217 (2012).
pubmed: 22644420
pmcid: 3413813
doi: 10.1007/s10974-012-9300-2
Grunnet, M. et al. KCNE4 is an inhibitory subunit to the KCNQ1 channel. J. Physiol. 542, 119–130 (2002).
pubmed: 12096056
pmcid: 2290389
doi: 10.1113/jphysiol.2002.017301
Shankar, T. S. et al. Cardiac-specific deletion of voltage dependent anion channel 2 leads to dilated cardiomyopathy by altering calcium homeostasis. Nat. Commun. 12, 4583 (2021).
pubmed: 34321484
pmcid: 8319341
doi: 10.1038/s41467-021-24869-0
Brosens, I. et al. The enigmatic uterine junctional zone: The missing link between reproductive disorders and major obstetrical disorders? Hum. Reprod. 25, 569–574 (2010).
pubmed: 20085913
doi: 10.1093/humrep/dep474
Cisneros, B. et al. Immune system modulation in aging: Molecular mechanisms and therapeutic targets. Front Immunol. 13, 1059173 (2022).
pubmed: 36591275
pmcid: 9797513
doi: 10.3389/fimmu.2022.1059173
Simmen, R. C. M. et al. The krüppel-like factors in female reproductive system pathologies. J. Mol. Endocrinol. 54, R89–R101 (2015).
pubmed: 25654975
pmcid: 4369192
doi: 10.1530/JME-14-0310
Marquez, C. M. D., Ibana, J. A. & Velarde, M. C. The female reproduction and senescence nexus. Am. J. Reprod. Immunol. 77, e12646 (2017).
López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M. & Kroemer, G. Hallmarks of aging: An expanding universe. Cell 186, 243–278 (2023).
pubmed: 36599349
doi: 10.1016/j.cell.2022.11.001
Fafián-Labora, J. A. & O’Loghlen, A. Classical and Nonclassical Intercellular Communication in Senescence and Ageing. Trends Cell Biol. 30, 628–639 (2020).
pubmed: 32505550
doi: 10.1016/j.tcb.2020.05.003
Ding, S., Merkulova-Rainon, T., Han, Z. C. & Tobelem, G. HGF receptor up-regulation contributes to the angiogenic phenotype of human endothelial cells and promotes angiogenesis in vitro. Hemost. Thromb. Vasc. Biol. https://doi.org/10.1182/blood-2002 (2003).
Ahluwalia, A. et al. Reduced NGF in Gastric Endothelial Cells Is One of the Main Causes of Impaired Angiogenesis in Aging Gastric Mucosa. CMGH 6, 199–213 (2018).
pubmed: 29992182
pmcid: 6037903
Carbone, C. et al. Angiopoietin-like proteins in angiogenesis, inflammation and cancer. Int J. Mol. Sci. 19, 431 (2018).
pubmed: 29389861
pmcid: 5855653
doi: 10.3390/ijms19020431
Ungvari, Z. et al. Endothelial dysfunction and angiogenesis impairment in the ageing vasculature. Nat. Rev. Cardiol. 15, 555–565 (2018).
pubmed: 29795441
pmcid: 6612360
doi: 10.1038/s41569-018-0030-z
Hessler, S. C. et al. Myometrial artery calcifications and aging. Menopause 22, 1285–1288 (2015).
pubmed: 25988797
doi: 10.1097/GME.0000000000000475
Pavord, S. & Maybury, H. How I treat postpartum hemorrhage. Blood https://doi.org/10.1182/blood-2014-10 (2015).
Cavalcante, M. B. et al. Dasatinib plus quercetin prevents uterine age-related dysfunction and fibrosis in mice. Aging 12, 2711–2722 (2020).
pubmed: 31955151
pmcid: 7041753
doi: 10.18632/aging.102772
Martin, I. V. et al. Platelet-derived growth factor (PDGF)-C neutralization reveals differential roles of PDGF receptors in liver and kidney fibrosis. Am. J. Pathol. 182, 107–117 (2013).
pubmed: 23141925
doi: 10.1016/j.ajpath.2012.09.006
Uutela, M. et al. PDGF-D induces macrophage recruitment, increased interstitial pressure, and blood vessel maturation during angiogenesis. Blood 104, 3198–3204 (2004).
pubmed: 15271796
doi: 10.1182/blood-2004-04-1485
Sun, W. et al. Regulation of the IGF1 signaling pathway is involved in idiopathic pulmonary fibrosis induced by alveolar epithelial cellsenescence and core fucosylation. Aging 13, 18852–18869 (2021).
pubmed: 34329195
pmcid: 8351684
doi: 10.18632/aging.203335
Craig, A. M. & Kang, Y. Neurexin-neuroligin signaling in synapse development. Curr. Opin. Neurobiol. 17, 43–52 (2007).
pubmed: 17275284
pmcid: 2820508
doi: 10.1016/j.conb.2007.01.011
Greenberg, M. B. et al. Does length of labor vary by maternal age? Am. J. Obstet. Gynecol. 197, 428.e1–7 (2007).
pubmed: 17904990
doi: 10.1016/j.ajog.2007.06.058
Wei, C. N., Deng, J. L., Dong, J. H., Ping, Z. P. & Chen, X. Z. The median effective dose of oxytocin needed to prevent uterine atony during cesarean delivery in elderly parturients. Drug Des. Devel Ther. 14, 5451–5458 (2020).
pubmed: 33335388
pmcid: 7737550
doi: 10.2147/DDDT.S258651
Liu, Y. et al. Single-cell RNA-seq reveals the diversity of trophoblast subtypes and patterns of differentiation in the human placenta. Cell Res 28, 819–832 (2018).
pubmed: 30042384
pmcid: 6082907
doi: 10.1038/s41422-018-0066-y
Carvalho, J. R. et al. Non-canonical Wnt signaling regulates junctional mechanocoupling during angiogenic collective cell migration. Elife 8, e45853 (2019).
pubmed: 31246175
pmcid: 6684320
doi: 10.7554/eLife.45853
Yamaguchi, M. et al. Calcitonin Receptor Signaling Inhibits Muscle Stem Cells from Escaping the Quiescent State and the Niche. Cell Rep. 13, 302–314 (2015).
pubmed: 26440893
doi: 10.1016/j.celrep.2015.08.083
Dagdeviren, S. et al. IL-10 prevents aging-associated inflammation and insulin resistance in skeletal muscle. FASEB J. 31, 701–710 (2017).
pubmed: 27811060
doi: 10.1096/fj.201600832R
Coughlin, S. et al. An extracatalytic function of CD45 in B cells is mediated by CD22. Proc. Natl Acad. Sci. USA 112, E6515–E6524 (2015).
pubmed: 26561584
pmcid: 4664364
doi: 10.1073/pnas.1519925112
McNerney, M. E., Guzior, D. & Kumar, V. 2B4 (CD244)-CD48 interactions provide a novel MHC class I-independent system for NK-cell self-tolerance in mice. Blood 106, 1337–1340 (2005).
pubmed: 15870174
pmcid: 1895194
doi: 10.1182/blood-2005-01-0357
Jinna, N. et al. The DARC Side of Inflamm-Aging: Duffy Antigen Receptor for Chemokines (DARC/ACKR1) as a Potential Biomarker of Aging, Immunosenescence, and Breast Oncogenesis among High-Risk Subpopulations. Cells 11, 3818 (2022).
pubmed: 36497078
pmcid: 9740232
doi: 10.3390/cells11233818
Nair, R. R., Madiwale, S. V. & Saini, D. K. Clampdown of inflammation in aging and anticancer therapies by limiting upregulation and activation of GPCR, CXCR4. NPJ Aging Mech. Dis. 4, 9 (2018).
pubmed: 30181898
pmcid: 6117261
doi: 10.1038/s41514-018-0028-0
Mendelson, C. R., Gao, L. & Montalbano, A. P. Multifactorial Regulation of Myometrial Contractility During Pregnancy and Parturition. Front Endocrinol. 10, 714 (2019).
doi: 10.3389/fendo.2019.00714
Zhang, L., Mamillapalli, R., Habata, S., McAdow, M. & Taylor, H. S. Myometrial-derived CXCL12 promotes lipopolysaccharide induced preterm labour by regulating macrophage migration, polarization and function in mice. J. Cell Mol. Med. 26, 2566–2578 (2022).
pubmed: 35318804
pmcid: 9077289
doi: 10.1111/jcmm.17252
Boros-Rausch, A., Shynlova, O. & Lye, S. J. A broad-spectrum chemokine inhibitor blocks inflammation-induced myometrial myocyte–macrophage crosstalk and myometrial contraction. Cells 11, 128 (2022).
Davezac, M. et al. Estrogen Receptor and Vascular Aging. Front. Aging 2, 727380 (2021).
pubmed: 35821994
pmcid: 9261451
doi: 10.3389/fragi.2021.727380
Anamthathmakula, P. et al. Estrogen receptor alpha isoform ERdelta7 in myometrium modulates uterine quiescence during pregnancy. EBioMedicine 39, 520–530 (2019).
pubmed: 30502052
doi: 10.1016/j.ebiom.2018.11.038
Peavey, M. C. et al. Progesterone receptor isoform B regulates the Oxtr-Plcl2-Trpc3 pathway to suppress uterine contractility. PNAS 118, e2011643118 (2021).
pubmed: 33707208
pmcid: 7980420
doi: 10.1073/pnas.2011643118
Bhartiya, D., Patel, H., Kaushik, A., Singh, P. & Sharma, D. Endogenous, tissue-resident stem/progenitor cells in gonads and bone marrow express FSHR and respond to FSH via FSHR-3. J. Ovarian Res. 14, https://doi.org/10.1186/s13048-021-00883-0 (2021).
Novellas, S. et al. MRI characteristics of the uterine junctional zone: From normal to the diagnosis of adenomyosis. Am. J. Roentgenol. 196, 1206–1213 (2011).
Kissler, K. & Hurt, K. J. The Pathophysiology of Labor Dystocia: Theme with Variations. Reprod. Sci. https://doi.org/10.1007/s43032-022-01018-6 (2022).
Elmes, M. et al. Maternal age effects on myometrial expression of contractile proteins, uterine gene expression, and contractile activity during labor in the rat. Physiol. Rep. 3, e12305 (2015).
pubmed: 25876907
pmcid: 4425948
doi: 10.14814/phy2.12305
Sheen, J. J. et al. Maternal age and risk for adverse outcomes. Am. J. Obstet. Gynecol. 219, 390.e1-390.e15 (2018).
Mas, A. et al. Identification and characterization of the human leiomyoma side population as putative tumor-initiating cells. Fertil. Steril. 98, 741–751.e6 (2012).
pubmed: 22633281
doi: 10.1016/j.fertnstert.2012.04.044
Slyper, M. et al. A single-cell and single-nucleus RNA-Seq toolbox for fresh and frozen human tumors. Nat. Med. 26, 792–802 (2020).
pubmed: 32405060
pmcid: 7220853
doi: 10.1038/s41591-020-0844-1
De Micheli, A. J., Spector, J. A., Elemento, O. & Cosgrove, B. D. A reference single-cell transcriptomic atlas of human skeletal muscle tissue reveals bifurcated muscle stem cell populations. Skelet. Muscle 10, 19 (2020).
pubmed: 32624006
pmcid: 7336639
doi: 10.1186/s13395-020-00236-3
Litviňuková, M. et al. Cells of the adult human heart. Nature 588, 466–472 (2020).
pubmed: 32971526
pmcid: 7681775
doi: 10.1038/s41586-020-2797-4
Wilk, A. J. et al. A single-cell atlas of the peripheral immune response in patients with severe COVID-19. Nat. Med 26, 1070–1076 (2020).
pubmed: 32514174
pmcid: 7382903
doi: 10.1038/s41591-020-0944-y
Deng, C. C. et al. Single-cell RNA-seq reveals fibroblast heterogeneity and increased mesenchymal fibroblasts in human fibrotic skin diseases. Nat. Commun. 12, 3709 (2021).
pubmed: 34140509
pmcid: 8211847
doi: 10.1038/s41467-021-24110-y
Schupp, J. C. et al. Integrated Single-Cell Atlas of Endothelial Cells of the Human Lung. Circulation 144, 286–302 (2021).
pubmed: 34030460
pmcid: 8300155
doi: 10.1161/CIRCULATIONAHA.120.052318
Garcia, F. J. et al. Single-cell dissection of the human brain vasculature. Nature 603, 893–899 (2022).
pubmed: 35158371
pmcid: 9680899
doi: 10.1038/s41586-022-04521-7
Geldhof, V. et al. Single cell atlas identifies lipid-processing and immunomodulatory endothelial cells in healthy and malignant breast. Nat. Commun. 13, 5511 (2022).
pubmed: 36127427
pmcid: 9489707
doi: 10.1038/s41467-022-33052-y
Winkler, E. A. et al. A single-cell atlas of the normal and malformed human brain vasculature. Science (1979) 375, eabi7377 (2022).
Yang, A. C. et al. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature 603, 885–892 (2022).
pubmed: 35165441
pmcid: 9635042
doi: 10.1038/s41586-021-04369-3
Wang, W. et al. Single-cell transcriptomic atlas of the human endometrium during the menstrual cycle. Nat. Med 26, 1644–1653 (2020).
pubmed: 32929266
doi: 10.1038/s41591-020-1040-z
Fonseca, M. A. S. et al. Single-cell transcriptomic analysis of endometriosis. Nat. Genet 55, 255–267 (2023).
pubmed: 36624343
doi: 10.1038/s41588-022-01254-1
Dann, E., Henderson, N. C., Teichmann, S. A., Morgan, M. D. & Marioni, J. C. Differential abundance testing on single-cell data using k-nearest neighbor graphs. Nat. Biotechnol. 40, 245–253 (2022).
pubmed: 34594043
doi: 10.1038/s41587-021-01033-z
Ma, Y. & Zhou, X. Spatially Informed Cell Type Deconvolution for Spatial Transcriptomics. Nat. Biotechnol. 40, 1349–1359 (2022).
pubmed: 35501392
doi: 10.1038/s41587-022-01273-7
Schneider, C. A., Rasband, W. S. & Eliceiri, K. W. NIH Image to ImageJ: 25 years of image analysis. Nat. Methods 9, 671–675 (2012).